Molecular Virology Research Group
PLEASE NOTE THIS SITE IS NO LONGER BEING UPDATED. The Stewart group website has moved to http://molecularvirology.org
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Electron Micrograph of Wood Mouse Herpesvirus
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Co-localisation of MHV-68 M2 with MHC class I on B lymphocytes
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MHV-68 vtRNA expression in splenic germinal centres of infected wood mice
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The Molecular Virology Research Group at the University of Liverpool, led by Prof. James Stewart, is focused on the use of molecular techniques to study the pathogenesis and immune response to the gamma subgroup of herpesviruses (?-herpesviruses). This group of viruses includes clinically important viruses that establish a life-long latent infection within lymphocytes. There are two human ?-herpesviruses, the Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), both of which establish latency in B lymphocytes. EBV is associated with infectious mononucleosis (glandular fever) as well as Burkitt's lymphoma and nasopharyngeal carcinoma. KSHV infection is detectable in virtually all Kaposi's sarcomas and B-cell primary effusion lymphomas. The most important animal ?-herpesviruses are the related Alcelaphine herpesvirus-1 and Ovine herpesvirus-2 (OvHV-2) that are associated with a fatal lymphoproliferative disease of domestic cattle and deer called malignant catarrhal fever (MCF). Infection of mice with the murine ?-herpesvirus, MHV-68 has been developed as a small animal model system. This system has enabled the study of key aspects of ?-herpesvirus infection in a natural host, in particular the detailed study of the fundamentals of virus-host interactions.
Murine ?-herpesvirus (MHV-68) MHV-68 is a natural pathogen of free-living murid rodents such as wood mice. Mice inoculated intranasally with MHV-68 establish a productive infection in the lung in alveolar epithelial cells causing an interstitial and peri-bronchiolar pneumonia. This productive phase of infection lasts for around 10 days, during which period the virus spreads via lymph nodes to the spleen. Here it establishes latency predominantly in B cells. This initial latent infection in the spleen causes an intense lymphoproliferation of B cells and T cells alike leading to splenomegaly. Although the precise mechanisms underlying splenomegaly are still being elucidated, it is clear that infected B cells and CD4+ 'helper' T cells are critical. Also, it is clear that a number of cytokines are secreted in abundance and this cytokine 'storm' almost certainly contributes towards driving lymphoproliferation. Latently infected cells appear in the first week post-infection, reach peak levels during the second to third week before declining to a basal level (1 in 106 leukocytes) that is maintained indefinitely in the host. Like most virus infections, T cells are critical for the immune-mediated resolution of infection. An important finding of this laboratory is that the spleen is not the only site of latency and that MHV-68 also persists indefinitely in lungs. The MHV-68 genome has 118kb of largely unique DNA flanked by terminal repeats and its complete DNA sequence has been determined recently. Of the 80 or so open-reading frames (ORFs) found, most are homologous to other g-herpesvirus or cellular genes. However, there are a number of ORFs, termed M1-4 that are unique, that is they have no obvious sequence relationship to virus or cellular genes recorded in current sequence databases.
Some publications
1. Hughes, D.J., Kipar, A., Sample, J.T.,Stewart J.P. (2010). Pathogenesis of a model gammaherpesvirus in its natural host. Journal of Virology. 84, 3949-3961.
2. Hughes, D.J., Kipar, A., Milligan, S., Cunningham, Saunders, M., Quail, M.A., Rajandream, M-A., Efstathiou, S., Bowden, R.J., Chastel, C., Bennett, M., Sample, J.T., Barrell, B., Davison, A.J. and Stewart, J.P. (2010). Characterization of a novel wood mouse virus related to murid herpesvirus 4. Journal of General Virology. 91, 867-879.
3. Meier-Trummer, C., Tobler, K., Hilbe, M., Stewart, J.P., Hart, J., Campbell, I., Haig, D.M., Glauser, D., Ehrensperger, F., Ackermann, M. (2009). Ovine herpesvirus-2 structural proteins in epithelial cells and M-cells of the appendix in rabbits with malignant catarrhal fever. Veterinary Microbiology. 137, 235-242.
4. Ottinger, M., Pliquet, D., Christalla, T., Frank, R.,Stewart, J.P., and Schulz, T.F. (2009). The interaction of the gammaherpesvirus 68 orf73 protein with cellular BET proteins is critical for the activation of cell cycle promoters. Journal of Virology. 83, 4423-4434
5. Jayawardane, G., Russell, G.C., Thompson, J., Deane, D., Cox, H., Gatherer, D., Ackermann, M., Haig, D.M., and Stewart J.P. (2008). A captured viral interleukin 10 gene with cellular exon Structure. Journal of General Virology. 89, 2447-2455.
6. Dry, I.,Haig, D.M., Inglis, N.F., Imrie, L., Stewart, J.P. and Russell, G.C. (2008). Proteomic analysis of pathogenic and attenuated Alcelaphine herpesvirus-1. Journal of Virology. 82, 5390-5397.
7. Anderson, I.E., Deane, D., Swa, S., Thomson, J., Campbell, I., Buxton, D., Wei, X-Q., Stewart, J.P, Russell, G. and Haig, D.M. (2008). Production and utilisation of interleukin-15 in malignant catarrhal fever. Journal of Comparative Pathology, 138, 131-144.
8. Stewart J.P., Kipar, A., Cox, H., Payne, C., Vasiliou, S., Quinn, J.P. (2008). Induction of tachykinin production in airway epithelia in response to viral infection. PLoS ONE. 3, e1673
9.Ehlers, B.,Kuechler, J., Yasmum, N., Dural, G., Voigt, S., Schmidt-Chanasit, J., Jäkel, T., Matuschka, F.-R., Richter, D., Essbauer, S., Hughes, D.J., Summers, C., Bennett, M., Stewart, J.P., and Ulrich, R. (2007). Identification of novel rodent herpesviruses including the first Gammaherpesvirus of Mus musculus. Journal of Virology. 81, 8091-8100.
11. Becker,S.D., Bennett, M., Stewart, J.P. and Hurst, J.L. (2007). Serological survey of virus infection among wild house mice (Mus domesticus) in the UK. Laboratory Animals. 41, 229-238
12.Hart, J.,Ackermann, M., Jayawardane, G., Russell, G., Haig, D.M., Reid, H. and Stewart, J.P. (2007). Complete sequence and analysis of the ovine herpesvirus 2 genome. Journal of General Virology. 88, 28-39.
13. Taus, N.S., Herndon, D.R., Traul, D.L., Stewart, J.P., Ackermann, M., Li, H., Knowles, D.P., Lewis, G.S. and Brayton, K.A. (2007). Comparison of ovine herpesvirus 2 genomes isolated from domestic sheep (Ovis aries) and a clinically affected cow (Bos bovis). Journal of General Virology. 88, 40-45.
Projects in the group include:
MHV-68 infection as a model for ?-herpesvirus pathogenesis and immunology
Molecular biology and pathogenesis of the Ovine Herpesvirus 2
Pathogenesis of respiratory syncytial virus (RSV) and Infelunza virus
The role of tachykinin neuropeptides in the host reponse to infection